EP3601261A1 - Protease-activated contrast agents for in vivo imaging - Google Patents
Protease-activated contrast agents for in vivo imagingInfo
- Publication number
- EP3601261A1 EP3601261A1 EP18777788.3A EP18777788A EP3601261A1 EP 3601261 A1 EP3601261 A1 EP 3601261A1 EP 18777788 A EP18777788 A EP 18777788A EP 3601261 A1 EP3601261 A1 EP 3601261A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- quencher
- alkyl
- optionally substituted
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108091005804 Peptidases Proteins 0.000 title claims abstract description 44
- 239000004365 Protease Substances 0.000 title claims abstract description 43
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 title claims abstract 3
- 239000002872 contrast media Substances 0.000 title abstract description 19
- 238000011503 in vivo imaging Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 93
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 241001465754 Metazoa Species 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 102000005600 Cathepsins Human genes 0.000 claims description 40
- 108010084457 Cathepsins Proteins 0.000 claims description 40
- -1 heterocyclylamino Chemical group 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 238000002372 labelling Methods 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 230000008685 targeting Effects 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- HIYWOHBEPVGIQN-UHFFFAOYSA-N 1h-benzo[g]indole Chemical compound C1=CC=CC2=C(NC=C3)C3=CC=C21 HIYWOHBEPVGIQN-UHFFFAOYSA-N 0.000 claims description 15
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 14
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 12
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 12
- 235000001014 amino acid Nutrition 0.000 claims description 12
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 11
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- 125000000539 amino acid group Chemical group 0.000 claims description 9
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 108090000624 Cathepsin L Proteins 0.000 claims description 8
- 102000004172 Cathepsin L Human genes 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229940124530 sulfonamide Drugs 0.000 claims description 7
- 150000003456 sulfonamides Chemical class 0.000 claims description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 6
- 102100026540 Cathepsin L2 Human genes 0.000 claims description 5
- 101000983577 Homo sapiens Cathepsin L2 Proteins 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 5
- 125000005239 aroylamino group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 5
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 5
- 102000035195 Peptidases Human genes 0.000 abstract description 41
- 230000000694 effects Effects 0.000 abstract description 29
- 230000002080 lysosomotropic effect Effects 0.000 abstract description 15
- 238000003776 cleavage reaction Methods 0.000 abstract description 14
- 230000007017 scission Effects 0.000 abstract description 14
- 238000001727 in vivo Methods 0.000 abstract description 11
- 238000001356 surgical procedure Methods 0.000 abstract description 9
- 238000002271 resection Methods 0.000 abstract description 8
- 239000012634 fragment Substances 0.000 abstract description 7
- 125000002091 cationic group Chemical group 0.000 abstract description 6
- 230000002132 lysosomal effect Effects 0.000 abstract description 4
- 238000012544 monitoring process Methods 0.000 abstract description 4
- 238000002675 image-guided surgery Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 description 100
- 239000000758 substrate Substances 0.000 description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000975 dye Substances 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 210000001519 tissue Anatomy 0.000 description 32
- 238000003384 imaging method Methods 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
- 229960004657 indocyanine green Drugs 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 27
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 27
- 125000001424 substituent group Chemical group 0.000 description 22
- 125000001183 hydrocarbyl group Chemical group 0.000 description 21
- 201000011510 cancer Diseases 0.000 description 19
- 125000005647 linker group Chemical group 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 13
- 239000007850 fluorescent dye Substances 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 12
- 230000007306 turnover Effects 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 11
- 235000018417 cysteine Nutrition 0.000 description 11
- 238000013461 design Methods 0.000 description 11
- 239000011347 resin Substances 0.000 description 11
- 229920005989 resin Polymers 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 238000012636 positron electron tomography Methods 0.000 description 9
- 206010006187 Breast cancer Diseases 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000010172 mouse model Methods 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 210000003712 lysosome Anatomy 0.000 description 7
- 230000001868 lysosomic effect Effects 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 5
- 238000000799 fluorescence microscopy Methods 0.000 description 5
- 239000012216 imaging agent Substances 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 4
- 108010006654 Bleomycin Proteins 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229960001561 bleomycin Drugs 0.000 description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 210000001072 colon Anatomy 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 125000003827 glycol group Chemical group 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000003068 molecular probe Substances 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- GJXXDQBMNMSDNT-UHFFFAOYSA-N 1,3-diphenoxypropan-2-one Chemical compound C=1C=CC=CC=1OCC(=O)COC1=CC=CC=C1 GJXXDQBMNMSDNT-UHFFFAOYSA-N 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 239000012099 Alexa Fluor family Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 3
- 102100025136 Macrosialin Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000004103 aminoalkyl group Chemical group 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000012632 fluorescent imaging Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 150000004668 long chain fatty acids Chemical group 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000012634 optical imaging Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 3
- 238000000163 radioactive labelling Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 150000007970 thio esters Chemical class 0.000 description 3
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000013170 computed tomography imaging Methods 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 230000005670 electromagnetic radiation Effects 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 238000012933 kinetic analysis Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- AWIJRPNMLHPLNC-UHFFFAOYSA-N methanethioic s-acid Chemical compound SC=O AWIJRPNMLHPLNC-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000003367 polycyclic group Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000000135 prohibitive effect Effects 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000000941 radioactive substance Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000001022 rhodamine dye Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000007974 sodium acetate buffer Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 1
- QZHGMNYYHDNFPX-UHFFFAOYSA-N 1,3-bis(2,3,4,5-tetrafluorophenoxy)propan-2-one Chemical compound FC1=C(F)C(F)=CC(OCC(=O)COC=2C(=C(F)C(F)=C(F)C=2)F)=C1F QZHGMNYYHDNFPX-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- VGIRNWJSIRVFRT-UHFFFAOYSA-N 2',7'-difluorofluorescein Chemical group OC(=O)C1=CC=CC=C1C1=C2C=C(F)C(=O)C=C2OC2=CC(O)=C(F)C=C21 VGIRNWJSIRVFRT-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- CEQFOVLGLXCDCX-UHFFFAOYSA-N 2-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000625 Cathepsin K Proteins 0.000 description 1
- 102000004171 Cathepsin K Human genes 0.000 description 1
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 1
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101000749287 Clitocybe nebularis Clitocypin Proteins 0.000 description 1
- 101000767029 Clitocybe nebularis Clitocypin-1 Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229940094664 Cysteine protease inhibitor Drugs 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241001125671 Eretmochelys imbricata Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 240000001973 Ficus microcarpa Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010056740 Genital discharge Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010050017 Lung cancer metastatic Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000014944 Lysosome-Associated Membrane Glycoproteins Human genes 0.000 description 1
- 108010064171 Lysosome-Associated Membrane Glycoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229910004727 OSO3H Inorganic materials 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical group [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- BDJDTKYGKHEMFF-UHFFFAOYSA-M QSY7 succinimidyl ester Chemical compound [Cl-].C=1C=C2C(C=3C(=CC=CC=3)S(=O)(=O)N3CCC(CC3)C(=O)ON3C(CCC3=O)=O)=C3C=C\C(=[N+](\C)C=4C=CC=CC=4)C=C3OC2=CC=1N(C)C1=CC=CC=C1 BDJDTKYGKHEMFF-UHFFFAOYSA-M 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000021375 Xenogenes Species 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- VCOVUYXJMHMVNV-FMYROPPKSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-5-(diaminomethylideneamino)-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C(=O)OCC1=CC=CC=C1 VCOVUYXJMHMVNV-FMYROPPKSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000012938 design process Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010891 electric arc Methods 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 238000012830 laparoscopic surgical procedure Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000010859 live-cell imaging Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002923 metal particle Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CEQFOVLGLXCDCX-WUKNDPDISA-N methyl red Chemical compound C1=CC(N(C)C)=CC=C1\N=N\C1=CC=CC=C1C(O)=O CEQFOVLGLXCDCX-WUKNDPDISA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000001472 pulsed field gradient Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000985 reactive dye Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002432 robotic surgery Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 238000004416 surface enhanced Raman spectroscopy Methods 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000979 synthetic dye Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- 238000007794 visualization technique Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000001018 xanthene dye Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- Contrast agents that target specific biomarkers in cancers can be used as intra-operative contrast agents to guide surgical resection of solid tumors in order to improve treatment outcome.
- optical based techniques utilizing fluorescent contrast agents have great potential.
- Indocyanine green (ICG), fluorescein, methylene blue, and 5- aminolevuliric acid (5 -ALA) are all non-targeted contrast agents that are currently approved as injectable enhancers for the visualization of various tumors.
- tumor-targeting agents such as Chlorotoxin-Cy5.5
- Chlorotoxin-Cy5.5 have been validated for optical imaging of malignant cancer cells using various mouse models of cancer. The mechanism of tumor selectivity for this agent is not, however, well understood. Veiseh et al. (2007) Cancer Res. 67:6882-8.
- An alternative approach to general tumor-targeted contrast agents is the use of so called “smart probes" that only produce or accumulate a signal in tumor tissues when acted upon by an enzyme activity that is associated with the tumor or surrounding margins.
- One useful strategy in smart probe design is to make probes that produce signal when cleaved by a protease. Because proteases play significant roles in tumor growth and metastasis as well as in diverse pathologies such as fibrosis, inflammation, osteoporoses, and arthritis, contrast agents that are activated by proteases could prove valuable for the detection and treatment of many diseases. Turk (2006) Nat. Rev. Drug Discov. 5:785-99; Drag and Salvesen (2010) Nat. Rev. Drug Discov. 9:690-701.
- MMPs matrix metallo proteases
- cysteine cathepsin activities are elevated in virtually all solid tumors due to increased infiltration of immune cells.
- the cysteine cathepsins have therefore been targeted in the design of tumor- specific contrast imaging agents.
- Such agents include fluorescent activity-based probes that covalently modify the cathepsins during turnover (Verdoes et al. (2013) /. Am. Chem. Soc.
- the probes employ an ester- linked acyloxymethyl ketone (AOMK) reactive group to modify the protease active site covalently.
- AOMK ester- linked acyloxymethyl ketone
- PCT International Publication No. WO 2014/145257 discloses quenched ABPs comprising an ether-linked, 2,3,5,6-tetrafluoro-substituted phenoxymethyl ketone (PMK) leaving element.
- the detectable component of the disclosed ABPs remain covalently attached to their target protease after enzymatic turnover.
- U.S. Patent Application Publication No. 2014/0301950 discloses imaging agents comprising a dark quencher, an amino acid backbone, a fluorophore, 6- aminohexanoic acid, aminoethoxyethoxy acetyl spacers, and a
- methoxypolyethylene glycol (mPEG) chain The agents are purportedly cleaved by cathepsins to generate a fluorescent signal and thus to image diseased cells.
- the technology is directed at identifying diseased cells at or near the surface of a tissue.
- D is a detectable element comprising a benzoindole dye
- Q is a quencher
- AA2 is an amino acid side chain
- U is O, NH, or S
- R is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or a protecting group, and is optionally substituted with 1 to 3 A groups;
- each A is independently alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, aroylamino, aralkanoylamin
- the benzoindole dye has the structure:
- o is an integer from 1 to 4.
- Ri is a C2-C8 alkyl group, optionally substituted with a sulfonate or carbonate;
- each R2 is independently a Ci-C 6 alkyl group
- L2 is an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- AA2 is an aralkyl amino acid side chain, optionally substituted with 1 to 3 A groups, and in some embodiments, U is O.
- Lo and Li is each independently an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- Lo and Li is each independently a C2-8 alkyl linker. Even more specifically, Li is a C 4 alkyl linker.
- Q is a QSY quencher, more specifically a hydrophilic QSY quencher, and even more specifically the hydrophilic QSY quencher is a sulfo-QSY quencher. In other specific embodiments, Q is QC-1.
- the compounds of the invention have structural formula (II):
- n' and n' ' is each independently an integer from 2-8; Ri is a QSY quencher or QC-1; and
- R2 is a benzoindole dye.
- n' may be 2, 4, or 6, or n' ' may be 4. Even more specifically, n' is 2, 4, or 6, and n" is 4
- a compound of the invention has the following structure:
- D is a detectable element comprising a benzoindole dye
- Lo is a linker
- T is a protease targeting element, optionally comprising a quencher; provided that Lo does not comprise an ethoxyethoxy spacer.
- T comprises a quencher.
- Lo is an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- Lo may be a C2-8 alkyl linker.
- the quencher may be a QSY quencher.
- the QSY quencher may be a hydrophilic QSY quencher, and more specifically, the hydrophilic QSY quencher may be a sulfo-QSY quencher.
- the quencher is QC-1.
- T is a peptidic targeting element.
- T contains no more than four amino acid residues.
- T is a cathepsin targeting element, optionally comprising a quencher. More specifically, T may be selective for cathepsin L or cathepsin V.
- T is
- AAi and AA2 is each independently an amino acid side chain
- U is O, NH, or S
- R is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or a protecting group, and is optionally substituted with 1 to 3 A groups;
- each A is independently alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, aroylamino, aralkanoylamin
- AAi is a basic amino acid side chain and AA2 is an aralkyl amino acid side chain, each optionally substituted with 1 to 3 A groups.
- U is O.
- T comprises a quencher.
- D comprises a radioactive substance
- AAi comprises a quencher. More specifically, AAi may be -Li-Q, wherein Li is a linker and Q is the quencher. In these embodiments, Li may more specifically be an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom. Even more specifically, Li may be a C2-8 alkyl linker such as a C 4 alkyl linker.
- AA2 is an aralkyl amino acid side chain, optionally substituted with 1 to 3 A groups.
- U is O.
- Q is a QSY quencher, such as a hydrophilic QSY quencher, or even a sulfo-QSY quencher.
- compositions for use in labeling a tissue in an animal comprise any of the above compounds, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the invention provides methods of labeling a tissue in an animal. These methods comprise the step of administering any of the above compositions to the animal.
- the invention provides methods of visualizing a tumor in an animal.
- the methods comprise the steps of:
- the detectable signal is associated with a diseased tissue in the animal.
- the detectable signal is a fluorescent signal. More specifically, the fluorescent signal is a near infrared signal.
- the detectable signal is generated at a tumor margin.
- the detectable signal is measured using an image-guided surgical device.
- FIGs. 1A - IB Design of cathepsin-selective protease substrate probes.
- FIG. IB Schematic representation of the latent lysosomotropic effect (LLE) introduced into the probe design in order to improved retention of the cleaved fluorescent products of probe cleavage.
- LLE latent lysosomotropic effect
- FIG. 2 Kinetic analysis of substrate cleavage by multiple cathepsins. Enzymatic turnover of quenched fluorescence nCQ and nQC substrates using recombinant cysteine cathepsins. The top trace in each panel corresponds to the activity with cathepsin L (Cat L). The next lower trace in each panel corresponds to the activity with cathepsin V (Cat V).
- FIGs. 3A - 3B Comparison of LLE and non-LLE substrates in vitro.
- FIG. 3A Effect of varying space length on cleavage efficiency (K C JKM) of quenched fluorescence nCQ and nQC substrates by recombinant cathepsin L.
- FIG. 3B Representative live cell fluorescence microscopy of RAW 264.7 cells incubated with 1 ⁇ of quenched fluorescence substrates (6CQ and 6QC).
- Red Punctate cytosolic staining in top two panels
- green Punctate cytosolic staining in middle two panels
- lysotracker a lysosome- selective stain
- blue nuclear staining in top two and middle two panels
- Merged fluorescence bottom two panels shows the overlap of the Cy5 staining and lysotracker staining.
- FIGs. 4A - 4C Validation of fluorescent substrates in the 4T1 breast cancer model.
- FIG. 4B Comparison of tumor labeling kinetics and pharmacokinetic properties of the non- lysosomotropic substrates, nCQ, and the lysosomotropic substrates, nQC, over a period of 24 hours.
- Error bars represent the standard deviation on the mean of N > 3 mice. Control mouse without probe was used to correct for auto-fluorescence.
- FIG. 4C Ex vivo tumor imaging at 4 hours and 24-hours post injection of the two types of substrate. Error bars represent the standard deviation on the mean of N > 3 mice.
- FIGs. 5A - 5B Confirmation of specific accumulation of the LLE substrate in tissues in vivo.
- FIG. 5A Histology on frozen sections of tumors excised from mice injected with substrates nCQ and nQC at the 24-hour endpoint. Cy5 fluorescence is shown in top panels (red staining; observed only in 2QC- treated and 6QC-treated animals), CD68 immunostaining for macrophages is shown in the middle panels (green staining; observed for all animals), DAPI
- FIG. 5B Biodistribution of probes in various organs 4 hours and 24 hours after intravenous administration. Error bars represent the standard deviation on the mean of N > 3 for each time point.
- FIGs. 6A - 6E Evaluation of in vivo properties of optimized NIR probes.
- FIG. 6A Chemical structures of the near infrared quenched non-lysosomotropic substrate 6CQNIR (8) and lysosomotropic analog 6QCNIR (9).
- FIG. 6B Time course of non-invasive fluorescence imaging of tumor associated cysteine cathepsins in breast cancer mouse model using NIR probes. Images are shown for 1, 2, 3, 4, 6, 12 and 24 hour time points. The bottom panels represent the optimal fluorescence contrasts for each probe at the particular time point.
- FIG. 6C Quantification of tumor labeling kinetics of 6CQNIR and 6QCNIR over the 24 hour time course. N > 3 mice for each probe.
- FIG. 6D Ex vivo images comparing tumors isolated from mice that received the two types of substrates. Isolation was at 4 hour and 24 hour time points.
- FIG. 6E Biodistribution of probes in various organs and tumors 24 hours after injection.
- FIGs. 7A - 7D Intraoperative fluorescence image guided detection and resection of colorectal, breast and lung adenocarcinomas, employing the clinical da Vinci surgical instrument in conjunction with a designed cathepsin probe.
- FIG. 7A Graphical illustration of the da Vinci surgical robot system equipped with a NIR camera.
- FIG. 7B Detection of polyps in the colon of colorectal cancer APC mm+ mouse model 6 hours after intravenous administration of LLE protease targeted contrast agent, 6QCNIR (9). Images were obtained from screenshots of the real time intraoperative imaging of the splayed colon.
- FIG. 7C Detection and fluorescent image guided surgical removal of mouse breast tumors (4T1) using the clinical instrument and the contrast agent 6QCNIR. The images compare white light illumination of tumor and tumor bed (left), fluorescence (center), and confirmation of malignancy of the tumor by H&E stain (right).
- FIG. 7D Application of the probes in the detection and resection of mouse lung cancer and correlation of cancer with histology.
- FIGs. 8A - 8C Design and validation of PET substrate probe for imaging cathepsins.
- FIG. 8A Structure of the substrate probe L0263.
- FIG. 8B Non- invasive PET/CT scans of mice treated with saline or bleomycin at Day 7 at 2 hours and 24 hours of imagining. Coronal (middle), transaxial (right) and sagittal (left) images are shown for representative mice from saline or bleomycin-treated groups at the indicated time points.
- FIGs. 9A - 9B Comparative time course of labeling tumors in mice using Dylight 780-labeled (FIG. 9A) or Indocyanine Green (ICG)-labeled (FIG. 9B) probes. Also shown in the right panels are more detailed kinetics of the tumor- labeling reactions.
- FIGs. 10A - 10B Comparative concentration-dependence of labeling tumors in mice using Dylight 780-labeled (FIG. 10A) or Indocyanine Green (ICG)- labeled (FIG. 10B) probes.
- FIGs. 11A - 11D Comparative ex vivo studies of animals labeled using Dylight 780-labeled (FIGs. 11A and 11C) or Indocyanine Green (ICG)-labeled (FIGs. 11B and 11D) probes. Detailed Description of the Invention
- modified peptides that contain either a quencher and fluorophore pair or a radioisotope label.
- the compounds release a fragment upon protease cleavage that contains the reporter (either the unquenched fluorophore or the radioisotope) and a protonable amine, thus resulting in enhanced lysosome retention of the released fragment.
- the compounds of the invention are useful for contrast imaging in any conditions that involve inflammation.
- the compounds find particular use in image-guided surgery of various solid tumors (breast, colon, lung, etc.), but are also useful in diagnosing and monitoring atherosclerosis, fibrosis, infectious diseases (e.g. , tuberculosis infections), and any condition where cathepsins, or other proteases, are secreted in an inflammatory response.
- the previous ABPs result in the covalent modification of the protease active site by the reactive probe during enzyme turnover.
- the fluorescent label remains covalently attached to the protease, and its latent fluorescence is unmasked by release of the portion of the probe containing the quencher during enzyme turnover.
- the current probes are a novel variation of the inventors' existing ABPs (Verdoes et al. (2013) /. Am. Chem. Soc. 135: 14726-30; PCT International Publication No. WO2014/145257) in which the PMK warhead has been replaced by a native amide bond that is cleavable by a protease (FIG. 1A).
- the length of the alkyl spacer between the substrate and the cleavage group has been varied in the new substrates, and the effects of placing the reporter fluorophore and the quencher in different locations on the substrates has been assessed.
- the instant disclosure provides novel compounds for use as imaging agents in the detection and imaging of protease activity, particularly the activity of cathepsins in animal tissues.
- the compounds have formula (I):
- D is a detectable element comprising a fluorescent label
- Q is a quencher
- AA2 is an amino acid side chain
- U is O, NH, or S
- R is alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or a protecting group, and is optionally substituted with 1 to 3 A groups;
- each A is independently alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, thio, amino, alkanoylamino, aroylamino, aralkanoylamin
- alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl- substituted alkyl groups.
- a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g. , C1-C30 for straight chains, C3-C30 for branched chains), and more specifically 20 or fewer.
- some cycloalkyls have from 3-10 carbon atoms in their ring structure, and more specifically have 5, 6 or 7 carbons in the ring structure.
- alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
- Such substituents can include, for example, a halo, a hydroxyl, a carbonyl (such as a keto, a carboxy, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a thio, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
- a halo such
- the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
- the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below.
- Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
- alkoxy refers to an alkyl group, in certain specific embodiments, a lower alkyl group, having an oxygen attached thereto.
- Representative alkoxy groups include methoxy, ethoxy, propoxy, i-butoxy, and the like.
- alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is contemplated.
- C x - y when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups that contain from x to y carbons in the chain.
- C x - y -alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight- chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
- Co-alkyl indicates a hydrogen where the group is in a terminal position, or is a bond if internal.
- C2- y -alkenyl and “C2- y -alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
- alkylamino refers to an amino group substituted with at least one alkyl group.
- alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-S-.
- alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is contemplated.
- amide refers to a group
- R x and R y each independently represent a hydrogen or hydrocarbyl group, or R x and R y taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
- amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g. , a moiety that can be represented by
- R x , R y , and R z each independently represent a hydrogen or a hydrocarbyl group, or R x and R y taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
- aminoalkyl refers to an alkyl group substituted with an amino group.
- aralkyl refers to an alkyl group substituted with an aryl group.
- aryl as used herein includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
- the ring is a 5- to 7-membered ring, and in more specific embodiments is a 6-membered ring.
- the term "aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g. , the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
- Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
- carboxylate is art-recognized and refers to a group wherein R x and R y independently represent hydrogen or a hydrocarbyl group, or R x and R y taken together with the atoms to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
- cycloalkyl refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
- a cycloalkyl ring contains from 3 to 10 atoms, and in more specific embodiments from 5 to 7 atoms.
- carbonate is art-recognized and refers to a group -OCC -R", wherein R x represents a hydrocarbyl group.
- esters refers to a group -C(0)OR x wherein R x represents a hydrocarbyl group.
- ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
- R x and R y independently represent hydrogen or a hydrocarbyl.
- heteroalkyl and “heteroaralkyl”, as used herein, refer to an alkyl group substituted with a hetaryl group.
- heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, in certain specific embodiments 5- to 7-membered rings, more specifically 5- to 6-membered rings, whose ring structures include at least one heteroatom, in some embodiments one to four heteroatoms, and in more specific embodiments one or two heteroatoms.
- heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g.
- the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
- Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
- heteroatom as used herein means an atom of any element other than carbon or hydrogen. Typical heteroatoms are nitrogen, oxygen, and sulfur.
- heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, in certain specific embodiments 3- to 10-membered rings, more specifically 3- to 7-membered rings, whose ring structures include at least one heteroatom, in some embodiments one to four heteroatoms, and in more specific embodiments one or two heteroatoms.
- heterocyclyl and heterocyclic also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g.
- the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
- Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
- heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
- Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
- hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
- lower when used in conjunction with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, and in certain embodiments, six or fewer.
- the acyl, acyloxy, alkyl, alkenyl, alkynyl, and alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, and lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
- polycyclyl refers to two or more rings (e.g. , cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g. , the rings are "fused rings".
- Each of the rings of the polycycle can be substituted or unsubstituted.
- each ring of the polycycle contains from 3 to 10 atoms in the ring, more specifically from 5 to 7.
- substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc., under conditions in which the compound is to be used. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
- the permissible substituents can be one or more and the same or different for appropriate organic compounds.
- the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
- Substituents may include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a keto, a carboxy, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
- references to chemical moieties herein are understood to include substituted variants.
- reference to an "aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
- sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
- R x and R y independently represent hydrogen or hydrocarbyl.
- sulfoxide is art-recognized and refers to the group -S(0)-R x , wherein R x represents a hydrocarbyl.
- sulfo or “sulfonate” is art-recognized and refers to the group - SO3H, or a pharmaceutically acceptable salt thereof.
- sulfone is art-recognized and refers to the group -S(0)2-R x , wherein R x represents a hydrocarbyl.
- thioalkyl refers to an alkyl group substituted with a thiol group.
- thioester refers to a group -C(0)SR x or - SC(0)R x wherein R x represents a hydrocarbyl.
- thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
- urea is art-recognized and may be represented by the general formula
- R x and R y independently represent hydrogen or a hydrocarbyl.
- the compounds of the instant invention are generally synthesized using standard synthetic chemical techniques, for example using the methods described in the Examples section below.
- Other useful synthetic techniques are described, for example, in March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Ed. , (Wiley, 2013); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols. A and B (Plenum 2000, 2001); Fiesers' Reagents for Organic Synthesis, Volumes 1-27 (Wiley, 2013); Rodd's Chemistry of Carbon
- the term "residue derived from” may be used to describe a residue formed by the reaction of a first reactive functional group on a first component and a second reactive functional group on a second component to form a covalent bond.
- an amine group on a first component may be reacted with an activated carboxyl group on a second component to form a residue including one or more amide moieties.
- Other permutations of first and second reactive functional groups are encompassed by the invention.
- the copper- catalyzed or copper-free reaction of an azide- substituted first component with an alkyne-substituted second component results in a triazole-containing residue through the well-known "click" reaction, as would be understood by those of ordinary skill in the art. See Kolb et al. (2001) Angew. Chem. Int. Ed. Engl.
- a protecting group is reversibly attached to a desired position of the molecule to control the reaction of other agents at that position.
- Protecting groups useful in the synthesis of the instant compounds are well known in the art. See, for example, Greene 's
- the Lo and Li groups of the instant compounds are linker groups that connect the detectable element, D, and the quencher, Q, respectively, to the subject compounds.
- Each linker group may independently be any suitable chemical linker, as would be understood by the person of ordinary skill in the art.
- the Lo and Li groups are preferably alkyl linker groups, wherein the alkyl linker is optionally substituted, and furthermore, wherein the carbons in the linker are optionally replaced by heteroatoms to the extent that the resulting structure is chemically stable.
- substitutions and replacements should be understood to include intervening groups within the linker such as ethers, thioethers, disulfides, esters, amides, carbonates, carbamates, and so forth.
- Preferred linkers range in length from 5 to 40 bonds and may be branched, straight-chain, or contain rings. Linkers may in some cases include double bonds. They may be hydrophobic or hydrophilic as desired, according to the particular requirements of the compound containing the linker.
- Lo and Li is each independently an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- Lo and Li is each independently a C2-8 alkyl linker.
- Li is a C 4 alkyl linker.
- connection between the Lo group and the detectable element, D, and between the Li group and the quencher, Q may be any suitable chemical connection, as would be understood by the skilled artisan.
- the instant compounds may in some cases be conveniently prepared by including in the delectable element or quencher precursor a moiety that is reactive with a particular chemical group, such as, for example, an amino group, a thiol group, or the like.
- the reactive detectable element or quencher can in such a situation be readily attached to the compound through the reaction of the amino group, the thiol group, or the like on the compound with the reactive group.
- the Li group in compounds of formula (I) may be modified to increase the half-life of the subject compounds in vivo.
- the Li group may therefore comprise a polyethylene glycol moiety, a palmitate or other long-chain fatty acid moiety, an albumin binding protein, or the like, in order to stabilize the modified compounds.
- the AAi and AA2 groups of the instant compounds may independently be any natural or unnatural amino acid side chain, as would be understood by the skilled artisan, or may be the group "-Li-Q".
- the AAi group is a basic amino acid side chain and the AA2 group is an aralkyl amino acid side chain, and each is optionally substituted with 1 to 3 A groups.
- the AAi group is a lysine side chain and the AA2 group is a phenylalanine side chain.
- the AAi group is -Li-Q and the AA2 group is an aralkyl amino acid side chain.
- the AAi group is a basic amino acid side chain and the AA2 group is -Li-Q.
- the AAi and AA2 groups are independently a side chain from an acidic amino acid residue, such as a side chain from an aspartic acid or glutamic acid residue, or a side chain from an alkyl amino acid residue, such as an alanine, leucine, isoleucine, valine, or other such amino acid residue, in any combination.
- Side chains from other amino acid residues such as lysine, arginine, tyrosine, glutamine, asparagine, and the like, are also suitable as either AAi or AA2 groups in the instant compounds.
- the Li linker component may be provided by an amino acid side chain.
- a lysine residue conveniently provides an amino-alkyl group for reaction with a suitably activated quencher.
- the U group is O.
- the R group is an alkyl group that is optionally substituted with 1 to 3 A groups. More specifically, the R group may be an alkyl group that is substituted with aryl that is itself optionally substituted. Even more specifically, the R group may be an optionally substituted aralkyl group such as, for example, a benzyl group.
- the detectable element, D, of the instant compounds is any chemical group capable of being detected by any suitable means, including without limit, optical, electrical, or chemical detection methods.
- the detectable element is a fluorescent label, a luminescent species, a phosphorescent species, a radioactive substance, including a positron-emitting substance, a nanoparticle, a SERS nanoparticle, a quantum dot or other fluorescent crystalline nanoparticle, a diffracting particle, a Raman particle, a metal particle, including a chelated metal, a magnetic particle, a microsphere, an RFID tag, a microbarcode particle, or a combination of these labels.
- the detectable element is a fluorescent label, a radiolabel, including a chelated metal, and the like.
- radiolabels and chelated metals suitable for use in these compounds are described in PCT International Publication No. 2009/124265, which is hereby incorporated by reference herein in its entirety.
- the detectable element is a fluorescent label.
- fluorescent labels emit electromagnetic radiation, preferably visible light or near infrared light, when stimulated by the absorption of incident electromagnetic radiation.
- a wide variety of fluorescent labels including labels having reactive moieties useful for coupling the label to reactive groups such as, for example amino groups, thiol groups, and the like, are commercially available. See, e.g. , The Molecular Probes ® Handbook— A Guide to Fluorescent Probes and Labeling Technologies, Life Technologies, Thermo Fisher Scientific, which is hereby incorporated by reference in its entirety.
- Other useful fluorescent reagents including a variety of near infrared (NIR) fluorescent labels, are available from Thermo Scientific Pierce Protein Biology Products, Rockford, IL.
- Near infrared fluorophores which typically absorb in the region of 700- 900 nm are particularly suitable for tissue imaging, as light of these wavelengths is capable of penetrating more deeply into tissues than light of shorter, for example visible, wavelengths.
- Exemplary near infrared fluorescent labels usefully employed in the compounds of the instant invention are the IRDye infrared dyes available from LI-COR Biosciences, Lincoln, NE. Non-limiting examples of these dyes are IRDye 800CW, IRDye 680RD, IRDye 680LT, IRDye 750, IRDye 700DX, IRDye 800RS, and IRDye 650.
- infrared dyes that are particularly well suited for in vivo imaging applications are the DyLight series of benzopyrillium and benzocyanine compounds, which are available from Thermo Scientific Pierce Protein Biology Products, Rockford, IL.
- Non-limiting examples of these dyes are DyLight 675-B1, DyLight 675-B2, DyLight 675-B3, DyLight 675-B4, DyLight 679-C5, DyLight 690-B 1, DyLight 690-B2, DyLight 700-B1, DyLight 700-B2, DyLight 730-Bl, DyLight 730-B2, DyLight 730-B3, DyLight 730-B4, DyLight 747-B1, DyLight 747-B2, DyLight 747-B3, DyLight 747-B4, DyLight 775-B2, DyLight 775-B3, DyLight 775-B4, DyLight 780-B l, DyLight 780-B2, DyLight 780-B3, DyLight 800, and DyLight 830-B2.
- Preferred near IR fluorophores are
- Fluorescein is a xanthene dye with an absorption maximum at 495 nanometers.
- a related fluorophore is Oregon green, a fluorinated derivative of fluorescein.
- bora-diaza-indecene bora-diaza-indecene, rhodamine, and cyanine dyes.
- bora-diaza-indecene dyes are represented by 4,4-difluoro-4-bora-3a,4a-diaza-s- indacene, known as the BODIPY ® dyes.
- BODIPY ® dyes 4,4-difluoro-4-bora-3a,4a-diaza-s- indacene.
- BODIPY ® dyes 4,4-difluoro-4-bora-3a,4a-diaza-s- indacene
- Various derivatives of these dyes are known and are considered suitable for use as a detectable element in the compounds of the instant disclosure. See, e.g. , Chen et al. (2000) /. Org. Chem. 65:2900-2906.
- Rhodamine dyes are a class of dyes based on the rhodamine ring structure.
- Rhodamines include, inter alia, tetramethylrhodamine (TMR), a very common fluorophore for preparing protein conjugates, especially antibody and avidin conjugates, and carboxy tetramethyl-rhodamine (TAMRA), a dye commonly used for oligonucleotide labeling and automated nucleic acid sequencing.
- TMR tetramethylrhodamine
- TAMRA carboxy tetramethyl-rhodamine
- Rhodamines are established as natural supplements to fluorescein- based fluorophores, which offer longer wavelength emission maxima and thus open opportunities for multicolor labeling or staining.
- Alexa Fluor dyes also included within the group of rhodamine dyes.
- Alexa Fluor dyes also included within the group of rhodamine dyes.
- Alexa Fluor dyes The dramatic advances in modern fluorophore technology are exemplified by the Alexa Fluor dyes, which were introduced by Molecular Probes.
- These sulfonated rhodamine derivatives exhibit higher quantum yields for more intense fluorescence emission than spectrally similar probes, and have several additional improved features, including enhanced photostability, absorption spectra matched to common laser lines, pH insensitivity, and a high degree of water solubility.
- the cyanine dyes correspond to a family of related dyes, Cy2, Cy3, Cy5, Cy7, and their derivatives, that are based on the partially saturated indole nitrogen heterocyclic nucleus with two aromatic units being connected via a polyalkene bridge of varying carbon number. These probes exhibit fluorescence excitation and emission profiles that are similar to many of the traditional dyes, such as fluorescein and tetramethylrhodamine, but with enhanced water solubility, photostability, and higher quantum yields. Most of the cyanine dyes are more environmentally stable than their traditional counterparts, rendering their fluorescence emission intensity less sensitive to pH and organic mounting media.
- the excitation wavelengths of the Cy series of synthetic dyes are tuned specifically for use with common laser and arc- discharge sources, and the fluorescence emission can be detected with traditional filter combinations.
- the cyanine dyes are readily available as reactive dyes or fluorophores.
- the cyanine dyes generally have broader absorption spectra than members of the Alexa Fluor family, making them somewhat more versatile in the choice of laser excitation sources for confocal microscopy.
- the detectable element of the instant compounds is the cyanine dye, Cy5.
- the detectable element comprises a benzoindole dye, such as indocyanine green ("ICG”) or a residue of indocyanine green:
- ICG indocyanine green
- Indocyanine green is used in various medical diagnostic applications, for example in monitoring and imaging certain cardiac, hepatic, ophthalmic, and circulatory conditions.
- indocyanine green and related compounds display absorption and emission spectra in the near infrared region.
- ICG absorbs primarily between 600 nm and 900 nm and emits primarily between 750 nm and 950 nm.
- Such wavelengths can penetrate biological tissues, thus enabling the imaging of these tissues using ICG and related compounds.
- the long-term and widespread use of ICG in medical diagnostic studies evidences the biocompatibility of these compounds.
- the detectable element comprises a benzoindole dye h
- o is an integer from 1 to 4.
- Ri is a C2-C8 alkyl group, optionally substituted with a sulfonate or carbonate;
- each R2 is independently a Ci-C 6 alkyl group
- L2 is an optionally substituted alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- the benzoindole dye can have the structure:
- Benzoindole-containing dyes can be synthesized for example as described in Zhang et al. (2005) Chem. Commun. 2005:5887 (DOI: 10.1039/b512315a). See also U.S. Patent Application Publication No. 2009/0214436 Al.
- L2 is an optionally substituted lower alkyl linker, wherein each carbon atom is optionally replaced with a heteroatom.
- the fluorescent label used in the detectable element of the compounds of the instant invention may be a pH-dependent fluorophore.
- fluorescent labels display a fluorescence spectrum that depends on the pH of the label's environment, as would be understood by the skilled artisan, and may therefore be useful in reporting information about the environment of the label following reaction, for example information about the location of or type of protease labeled by the reactive compound.
- the pH-dependent fluorescence of various labels usefully included in the detectable element of the instant compounds is well known. See, e.g. , The Molecular Probes ® Handbook— A Guide to
- detectable groups e.g. , fluorescent labels, radiolabels, chelated metals, and the like
- detectable groups e.g. , fluorescent labels, radiolabels, chelated metals, and the like.
- Such multiple labeling can be achieved using routine coupling chemistry as would be understood by the skilled artisan.
- the compounds of the instant specification typically also comprise a quencher group, Q.
- quencher refers to a chemical entity that modulates the emission of a fluorophore.
- a quencher may itself be a fluorescent molecule that emits fluorescence at a characteristic wavelength distinct from the label whose fluorescence it is quenching.
- a fluorophore may act as a quencher when appropriately coupled to another dye and vice versa.
- the increase in fluorescence from the acceptor molecule which is of a different wavelength to that of the donor label, may separately report interactions of the labeled compound with its environment, such as, for example, the interior of a lysosome or other cellular compartment.
- the quencher does not itself fluoresce (i.e. , the quencher is a "dark acceptor").
- quenchers include, for example, dabcyl, methyl red, the QSY diarylrhodamine dyes, and the like.
- dabcyl (4-dimethylamino-phenylazo)benzoic acid
- U.S. Patent No. 5,989,823 Diazo dyes of the BHQ series, which are referred to as "Black Hole Quenchers", provide a broad range of absorption which overlaps well with the emission of many fluorophores.
- QSY 7 in particular is a nonfluorescent diarylrhodamine derivative.
- QSY21 is a nonfluorescent diarylrhodamine chromophore with strong absorption in the visible spectrum, and is an effective fluorescence quencher.
- Sulfo-QSY21 is a sulfonate version of
- IRDye QC-1 (available from Li-Cor) is another example of a nonfluorescent dye that is suitable for use as a quencher in the instant compounds (see FIG. 6A). It efficiently quenches fluorescence from a wide range of fluorophores, including those ranging in wavelength from the visible region to the near-infrared.
- n' and n" is each independently an integer from 2-8;
- Ri is a QSY quencher or QC-1
- R2 is a benzoindole dye.
- n" is 4.
- n' is 2, 4, or 6.
- the compound has the following structural formula:
- D is a detectable element comprising a benzoindole dye
- Lo is a linker
- T is a protease targeting element, optionally comprising a quencher; provided that Lo does not comprise an ethoxyethoxy spacer.
- the protease targeting element, T, in compounds of formula (III) is any suitable chemical structure that is capable of being recognized by a protease and catalytically hydrolyzed by the protease to release a lysosomotropic fragment, D- L0-NH3 "1" .
- Examples of such structures, including peptidic and non-peptidic protease targeting elements without limitation, are well known in the art of protease enzymology.
- the protease targeting element is a peptidic structure that contains no more than four amino acid residues or no more than three amino acid residues.
- the protease targeting element is a peptidic structure that contains no more than two amino acid residues.
- the compounds of formula (I), as shown above, comprise a protease targeting element that contains two amino acid residues.
- the protease targeting element is a structure that is selective for cleavage by cathepsin, and in particular by cathepsin L or cathepsin V.
- the T group in compounds of formula (III) may be modified to increase the half-life of the subject compounds in vivo.
- the T group may therefore comprise a polyethylene glycol moiety, a palmitate or other long-chain fatty acid moiety, an albumin binding protein, or the like, in order to stabilize the modified compounds.
- Lo does not comprise a polyethylene glycol group.
- the protease targeting element is , wherein
- AAi and AA2 is each independently an amino acid side chain, U is O, NH, or S, and
- R is as defined above for compounds of formula (I).
- AAi is a basic amino acid side chain and AA2 is an aralkyl amino acid side chain, each optionally substituted with 1 to 3 A groups.
- U is O.
- the R group is an aralkyl group such as, for example, a benzyl group.
- AAi comprises a quencher.
- AAi may have the structure -Li-Q, wherein Li is a linker as defined above, and Q is a quencher.
- the Li group may be modified to increase the half-life of the subject compounds in vivo.
- the Li group may therefore comprise a polyethylene glycol moiety, a palmitate or other long- chain fatty acid moiety, an albumin binding protein, or the like, in order to stabilize the modified compounds.
- the caspase targeting element, T, in compounds of formula (III) comprises a quencher.
- the Lo linker group in compounds of formula (III) may be any of the linkers described above.
- the instant invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.
- Such compositions are useful, for example, in the imaging of tissues in an animal and are further useful in assessing the activity of enzymes in the animal, for example, protease enzymes.
- the pharmaceutical compositions may usefully serve as agents for the non-invasive optical imaging of cancer cells.
- compositions include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
- aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
- the aqueous solution is pyrogen free, or substantially pyrogen free.
- the excipients may be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
- the pharmaceutical composition may be in dosage unit form such as tablet, capsule, sprinkle capsule, granule, powder, syrup, suppository, injection or the like.
- the composition may also be present in a transdermal delivery system, e.g. , a skin patch.
- a pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize or to increase the absorption of a compound of the instant invention.
- physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
- the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
- the pharmaceutical composition also may comprise a liposome or other polymer matrix, which may have incorporated therein, for example, a compound of the invention. Liposomes, for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject compounds from one organ, or portion of the body, to another organ, or portion of the body.
- a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject compounds from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
- a pharmaceutical composition containing a compound of the instant invention may be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, boluses, powders, granules, pastes for application to the tongue); sublingually; anally, rectally, or vaginally (for example, as a pessary, cream, or foam); parenterally (including intramuscularly, intravenously, subcutaneously, or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); or topically (for example, as a cream, ointment or spray applied to the skin).
- routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, boluses, powders, gran
- the compound may also be formulated for inhalation.
- a compound of the instant invention may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Patent Nos. 6,110,973; 5,763,493; 5,731,000; 5,541,231; 5,427,798;
- the disclosure provides methods of labeling a tissue in an animal, comprising the step of administering a composition of the invention to the animal.
- the disclosure provides methods of visualizing a tumor in an animal, comprising the steps of administering a composition of the invention to the animal, and measuring a detectable signal generated in the animal from a reaction of the composition with a protease, specifically a cysteine protease, wherein the detectable signal is associated with a tumor in the animal.
- the detectable signal is a fluorescent signal.
- the fluorescent signal is generated at a tumor margin.
- peptide imaging agents administered to an animal is well understood by those of ordinary skill in the art.
- the agent is administered by injection, although any other suitable means of administration is considered within the scope of the invention.
- the methods of the invention are directed at the labeling and visualization of a protease, in particular a cysteine protease, in an animal.
- Suitable animals include animals expressing cysteine proteases, particularly in tumor cells.
- the animal is a mammal.
- the animal is a mammal.
- the animal is a human. In other preferred embodiments, the animal is a livestock animal or a pet.
- the methods of the invention comprise the step of measuring a detectable signal generated in the animal.
- Methods of measuring the detectable signal include, but are not limited to, imaging methods, for example fluorescent imaging methods.
- the fluorescent imaging system is, for example, a Xenogen IVIS 100 system, an IVIS Spectrum system (PerkinElmer, Waltham, MA), or any other suitable non-invasive, in vivo fluorescence imaging system.
- the detectable fluorescent signal is measured using a da Vinci Surgical System (Intuitive Surgical, Inc.,
- Such systems may be used to implement the instant labeling and visualization methods in combination with intraoperative fluorescence-guided surgical techniques in patient tissues treated with the instant imaging agents.
- the instant specification provides compounds for use in labeling a tissue in an animal.
- the compounds are described in detail above. These compounds, in combination with a pharmaceutically acceptable carrier, are administered to the animal in order to label the tissue.
- the compounds are also provided for use in visualizing a tumor in an animal. As above, the compounds, in combination with a pharmaceutically acceptable carrier, are administered to the animal, and a detectable signal generated in the animal from a reaction of the compound with a protease, specifically a cysteine protease, is measured in order to visualize the tumor.
- the lengths of the alkyl spacer between the substrate and the quencher were varied in order to measure the effect of the spacer length on the cleavage/unquenching efficiency of the probes by cathepsins.
- Sulfo-QSY21-NHS or Cy5-NHS was coupled to the free terminal amine of the separate halves in DMSO, followed by the removal of the Boc -protective group on the lysine in 50 % TFA in DCM.
- the final quenched substrates were obtained by coupling either Cy5-NHS (for the nCQ substrates) or sulfo-QSY21-NHS (for the nQC substrates) onto the lysine side chain. After purification by HPLC, the probes were tested for activity against various recombinant cysteine cathepsins in vitro.
- the substrates were next assessed in a syngeneic, orthotopic mouse model of breast cancer.
- 4T1 cells are inoculated into the left number 1 and 10 mammary fat pad of mice to generate tumors.
- imaging signals of lysosomotropic probes 2QC (compound 5) and 6QC (compound 7) were directly compared to those of the non-lysosomotropic analogues 2CQ (compound 2) and 6CQ (compound 4).
- Substrates were administered to tumor-bearing mice intravenously, and mice were imaged at various time points following the administration.
- the Da Vinci surgical system is a robotic surgical system manufactured by Intuitive Surgical Inc. that is currently used in clinics all over the world for laparoscopic surgery. Surgical procedures using this system are currently performed under white light illumination, however, which does not provide sufficient contrast to demarcate the margins of tumors from the surrounding normal tissues.
- the development of a tumor-targeted contrast agent that is also compatible with the existing Da Vinci system is therefore of great value, and should result in markedly improved treatment outcomes in fluorescence-guided surgery (FGS).
- the QSY21-sulfo quencher was also substituted with IRDye QC-1, which is a dark NIR quencher (FIG. 6A).
- the emission wavelength of the NIR dye (absorption/emission maxima of 783/799 nm) falls within a window with low overall background and will therefore enhance tissue penetration and improve signal to background ratio during imaging.
- Richards-Kortum and Sevick- Muraca (1996) Annu. Rev. Phys. Chem. 47:555-606.
- the NIR probes were first analyzed as contrast agents in the 4T1 breast cancer model described above, using the IVIS-spectrum imaging system.
- mice were imaged non-invasively every hour for 4 hours, and then at 6, 8, 12 and 24 hours post injection of the substrate.
- a rapid accumulation of the probe signal was observed in the implanted breast tumors.
- substantial contrast that demarcated the tumor margin from healthy surrounding tissues was observed as early as 1-hour post injection of both probes (FIG. 6B).
- the intensity of the fluorescence signal in the tumors increased rapidly in mice injected with both types of probes, and it eventually peaked between 4 to 6 hours. This time- point may signify an optimum window for imaging tumors following systemic administration of this class of non-covalent quenched fluorescent probes.
- the near infrared analogs showed a lysosomal trapping effect as evidence by the slower clearance rate and brighter signal in tumors of mice injected with the LLE substrate 6QCNIR relative to the non-LLE substrate (FIGs. 6B and 6C) and after ex vivo analysis of tumors (FIG. 6D). Between 1 and 4 hours, both substrates showed similar initial intensity, indicating that the activation rates of both substrates by cathepsins are equal. Similar to the Cy5 probes, the NIR analogues were eliminated by renal clearance, as the highest signal accumulation was observed in the kidneys and in tumors (FIG. 6E).
- FIG. 7A This robotic surgery system
- FIG. 7B Surgical resections on models of colon cancer (APC mice; FIG. 7B) were chosen, as well as breast cancer (4T1 transplant model; FIG. 7C) and a model of metastatic lung cancer (FIG. 7D).
- the da Vinci robot was used to perform a resection of positive probe signals. Tissues were also removed from the animals in order to performed histological analysis and thus to confirm the presence of cancer cells in the substrate-positive tissues.
- FIGs. 8A - 8C show the structure of a cathepsin probe containing a chelator in the leaving group and the use of the PET substrate probe for imaging cathepsin activity in animals.
- Uses of similar probes to monitor the contribution of macrophages to fibrotic disease progression in the bleomycin-induced murine model of pulmonary fibrosis, to image activated macrophage populations in murine models of atherosclerosis, and to topically label human carotid plaques have recently been reported. See Withana et al. (2016) Sci. Rep. 6: 19755 and Withana et al. (2016) /. Nucl. Med. 57: 1583-1590, each of which is incorporated by reference herein in its entirety.
- Scheme 1 summarizes the synthesis of the initial series of fluorescent substrates used in these studies.
- the resin was then washed with DCM and then suspended in methanol for 10 minutes in order to deactivate unreacted trityl-chloride.
- Fmoc deprotection was achieved by suspending the resin in a solution of 20 % piperidine in DMF for duration of 1 hour, followed by 3 times wash with DCM and DMF respectively.
- the first amino acid Fmoc-Lys(Boc)-OH (0.58 g, 1.26 mmol) was coupled to the resin using HBTU (0.48 g, 1.26 mmol) and DIPEA (0.17 g, 1.26 mmol) in 3 mL DMF and rotating the mixture for 2 h.
- Substrates 2QC, 4QC, and 6QC (Compounds 5, 6, and 7) [0167] In a separate 1 mL eppendorf tubes, intermediates la (2.0 mg, ⁇ ), lb (2.0 mg, ⁇ ) and lc (2.0 mg, ⁇ ) were dissolved in 100 of DMSO.
- 64 Cu-L0263 was prepared by incubation of ⁇ . L0263 (lOmM) (FIG. 8A) in 90 ⁇ sodium acetate buffer (0.1M, pH 5.5) with 4 mCi of 64 CuCl 2 in ⁇ sodium acetate buffer (0.1M, pH 5.5) at 37 °C for 1 hour. After cooling to room temperature, the reaction mixture was analyzed by RP-HPLC. The 64 Cu- L0263 was then purified by RP- HPLC with the mobile phase starting from 95% solvent A (di-water with 0.1% TFA) and 5% solvent B (acetonitrile with 0.1% TFA) for 3 min to 5% solvent A and 95% solvent B at 23 min.
- the eluted fractions containing 64 Cu-L0263 were then collected and dried using a rotary evaporator.
- the radiolabeling yield was 90% (calculated from the HPLC).
- the radiochemical purity, defined as the ratio of the main product peak to other peaks, was determined by radio-HPLC to be >95%, and the specific activity of the probe was determined to be 3-4 Ci/mmol.
- the 64 Cu-L0263 was then reconstituted in 0.9% saline and passed through a 0.22 ⁇ Millipore filter into a sterile vial for animal PET/CT imaging. PET In Vivo Imaging
- mice were intravenous injected with 100 ⁇ of 64 Cu-L0263 and imaged after 2h, and 24 h by using Inveon small-animal PET/CT (Siemens) (FIG. 8B). Briefly, a CT anatomic image scan was acquired (80 kV, 500 ⁇ ) with a pixel size of approximately 0.1 mm. After CT imaging, whole-body PET imaging was performed with 5 min static scan. The PET images were reconstructed using the ordered-subsets expectation maximization 3 -dimensional algorithm based on CT attenuation and analyzed using the Inveon Research Workplace (IRW) software (Siemens). PET voxel size was 0.796 x 0.861 x 0.861 mm, for a total of 128 x 128 x 159 voxels. Then PET/CT quantify assay was performed, and tissue
- radioactivity was calculated and expressed as decay-corrected percentage injected dose per gram of tissue (%ID/g). Investigators conducting the trial were blinded as to what groups were being imaged.
- An imaging probe comprising an indocyanine green detectable element
- the ICG-labeled probe shown above (ex/em: 805/835 nm) was compared to a Dylight 780-Bl-labeled probe (ex/em: 783/799 nm) in a mouse tumor model system.
- 4T1 breast cancer cells were injected into the fat pad of subject mice. Tumors were allowed to grow for 10-12 days, and the probes were then injected via the tail vein (3 doses: 10, 50, 100 nmol per mouse). Subject mice were then imaged on Licor PEARL (785/820 nm).
- FIGs. 10A and 10B Effect of probe concentration on fluorescence is illustrated in FIGs. 10A and 10B, where images of animals treated with 10 nmol, 50 nmol, and 100 nmol of the Dylight 780-labeled probe (FIG. 10A) are compared with images of animals treated with 10 nmol, 50 nmol, and 100 nmol of the ICG-labeled probe (FIG. 10B).
- the fluorescent output resulting from treatment with the ICG-labeled probe is significantly higher than that resulting from treatment with the Dylight 780-labeled probe.
- FIGs. 11A-11D The differences in signal between the two probes was further quantified by ex vivo studies, as illustrated in FIGs. 11A-11D, where animals treated with 10 nmol, 50 nmol, and 100 nmol of each of the Dylight 780-B1- and ICG-labeled probes were sacrificed at 8 hours, and the fluorescence associated with various animal tissues was quantified.
- FIGs. 11A and 11B compare whole-body images of animals treated with the Dylight 780-labeled probe (FIG. 11 A) or the ICG-labeled probe (FIG. 11B) at the three concentrations after 8 hours of labeling.
- FIGs. 11A and 11B compare whole-body images of animals treated with the Dylight 780-labeled probe (FIG. 11 A) or the ICG-labeled probe (FIG. 11B) at the three concentrations after 8 hours of labeling.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Optics & Photonics (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biodiversity & Conservation Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762478639P | 2017-03-30 | 2017-03-30 | |
PCT/US2018/025567 WO2018183960A1 (en) | 2017-03-30 | 2018-03-30 | Protease-activated contrast agents for in vivo imaging |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3601261A1 true EP3601261A1 (en) | 2020-02-05 |
EP3601261A4 EP3601261A4 (en) | 2021-07-14 |
Family
ID=63678348
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP18777788.3A Pending EP3601261A4 (en) | 2017-03-30 | 2018-03-30 | Protease-activated contrast agents for in vivo imaging |
Country Status (6)
Country | Link |
---|---|
US (2) | US11828752B2 (en) |
EP (1) | EP3601261A4 (en) |
JP (1) | JP7149614B2 (en) |
KR (1) | KR102669535B1 (en) |
CN (1) | CN110678460A (en) |
WO (1) | WO2018183960A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022203930A1 (en) * | 2021-03-24 | 2022-09-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Fluorogenic cyanine carbamates |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL60888A (en) | 1978-06-16 | 1984-07-31 | Yeda Res & Dev | Substrates and process for the quantitative assay of enzymes |
US5055451A (en) | 1986-12-22 | 1991-10-08 | Syntex Inc. | Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors |
EP0840614A1 (en) | 1995-06-13 | 1998-05-13 | Sanofi Winthrop, Inc. | Calpain inhibitors for the treatment of neurodegenerative diseases |
US6544951B2 (en) | 1998-07-02 | 2003-04-08 | Idun Pharmaceuticals, Inc. | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US20020052323A1 (en) | 2000-08-30 | 2002-05-02 | Jinhai Wang | Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents |
GB0112868D0 (en) | 2001-05-25 | 2001-07-18 | Secr Defence | Detection system |
US7303741B2 (en) | 2002-09-23 | 2007-12-04 | General Electric Company | Systems and methods for high-resolution in vivo imaging of biochemical activity in a living organism |
US20060148014A1 (en) | 2004-12-09 | 2006-07-06 | Sergei Agoulnik | Tubulin isotype screening in cancer therapy using hemiasterlin analogs |
US8968700B2 (en) | 2005-08-11 | 2015-03-03 | The Board Of Trustees Of The Leland Stanford Junior University | Imaging of protease activity in live cells using activity based probes |
CN101652149B (en) | 2007-02-28 | 2012-11-14 | 塞诺菲-安万特股份有限公司 | Imaging probes |
BRPI0808046A2 (en) * | 2007-02-28 | 2014-07-08 | Sanofi Aventis | IMAGE PROBES |
AU2008285761A1 (en) | 2007-08-03 | 2009-02-12 | Sanofi-Aventis | Caspase imaging probes |
US20090214436A1 (en) | 2008-02-18 | 2009-08-27 | Washington University | Dichromic fluorescent compounds |
WO2009124265A1 (en) | 2008-04-03 | 2009-10-08 | The Board Of Trustees Of The Leland Stanford Junior University | Probes for in vivo targeting of active cysteine proteases |
US9155471B2 (en) | 2009-05-27 | 2015-10-13 | Lumicell, Inc'. | Methods and systems for spatially identifying abnormal cells |
WO2012021800A2 (en) | 2010-08-13 | 2012-02-16 | Banyan Biomarkers | Caspase inhibitors as therapeutics for neural and organ injury and imaging |
WO2012118715A2 (en) | 2011-02-28 | 2012-09-07 | The Board Of Trustees Of Leland Stanford Junior University | Non-peptidic quenched fluorescent imaging probes |
EP2686680B1 (en) | 2011-03-18 | 2018-06-13 | Biotium Inc. | Fluorescent dyes, fluorescent dye kits, and methods of preparing labeled molecules |
WO2013036743A1 (en) | 2011-09-09 | 2013-03-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Imaging agents for imaging protease activity and uses thereof |
US20140180073A1 (en) | 2012-12-24 | 2014-06-26 | Anticancer, Inc. | Portable digital imaging system for fluorescence-guided surgery |
US9763577B2 (en) | 2013-03-14 | 2017-09-19 | Lumicell, Inc. | Imaging agent for detection of diseased cells |
EP4218829A3 (en) | 2013-03-15 | 2023-08-16 | The Board of Trustees of the Leland Stanford Junior University | Activity-based probe compounds, compositions, and methods of use |
US9845493B2 (en) | 2013-04-19 | 2017-12-19 | Agency For Science, Technology And Research | Tunable fluorescence using cleavable linkers |
US20170050988A1 (en) * | 2013-11-25 | 2017-02-23 | Sanofi | Dotam derivatives for therapeutic use |
WO2016118910A1 (en) * | 2015-01-22 | 2016-07-28 | The Board Of Trustees Of The Leland Stanford Junior University | Protease-activated contrast agents for in vivo imaging |
-
2018
- 2018-03-30 JP JP2019553932A patent/JP7149614B2/en active Active
- 2018-03-30 EP EP18777788.3A patent/EP3601261A4/en active Pending
- 2018-03-30 CN CN201880035357.XA patent/CN110678460A/en active Pending
- 2018-03-30 KR KR1020197032178A patent/KR102669535B1/en active IP Right Grant
- 2018-03-30 US US16/499,734 patent/US11828752B2/en active Active
- 2018-03-30 WO PCT/US2018/025567 patent/WO2018183960A1/en unknown
-
2023
- 2023-10-18 US US18/489,653 patent/US20240077475A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2020513050A (en) | 2020-04-30 |
WO2018183960A1 (en) | 2018-10-04 |
US20240077475A1 (en) | 2024-03-07 |
KR20200002874A (en) | 2020-01-08 |
EP3601261A4 (en) | 2021-07-14 |
JP7149614B2 (en) | 2022-10-07 |
KR102669535B1 (en) | 2024-05-24 |
US11828752B2 (en) | 2023-11-28 |
CN110678460A (en) | 2020-01-10 |
US20210109090A1 (en) | 2021-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11655236B2 (en) | Activity-based probe compounds, compositions, and methods of use | |
US20240025945A1 (en) | Protease-activated contrast agents for in vivo imaging | |
AU2022202947B2 (en) | Activity-based probe compounds, compositions, and methods of use | |
US20240077475A1 (en) | Protease-activated contrast agents for in vivo imaging |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20191030 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Free format text: PREVIOUS MAIN CLASS: C07D0401140000 Ipc: C09B0023010000 |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20210616 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C09B 23/01 20060101AFI20210610BHEP Ipc: C09B 23/08 20060101ALI20210610BHEP Ipc: C07D 401/14 20060101ALI20210610BHEP Ipc: C12Q 1/37 20060101ALI20210610BHEP Ipc: C07K 4/00 20060101ALI20210610BHEP Ipc: C07D 403/06 20060101ALI20210610BHEP Ipc: C07D 403/14 20060101ALI20210610BHEP Ipc: G01N 33/532 20060101ALI20210610BHEP Ipc: G01N 33/58 20060101ALI20210610BHEP Ipc: C07K 5/065 20060101ALI20210610BHEP Ipc: A61K 49/00 20060101ALI20210610BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20240625 |